Synthesis, Biological Evaluation of 1,1-Diarylethylenes as a Novel Class of Antimitotic Agents

Abdallah Hamze (1) , Anne Giraud (1) , Samir Messaoudi (1) , Olivier Provot (1) , Jean-François Peyrat (1) , Jérôme Bignon (2) , Jian-Miao Liu (2) , Joanna Wdzieczak-Bakala (2) , Sylviane Thoret (2) , Joëlle Dubois (2) , Jean-Daniel Brion (1) , Mouad Alami (1)

1 BioCIS - Biomolécules : Conception, Isolement, Synthèse
2 ICSN - Institut de Chimie des Substances Naturelles

The cytotoxic activity of a series of 23 new isocombretastatin A derivatives with modifications on the Bring was studied. Several compounds exhibited excellent antiproliferative activity at a nanomolar concentration against a panel of human cancer cell lines. The most cytotoxic compounds, isoFCA4 (2e), isoCA4 (2k) and isoNH2CA4 (2s), strongly inhibited tubulin polymerization with IC50 values of 4, 2 and 1.5 µM, respectively. These derivatives were found to be 10-fold more active than phenstatin and colchicine in the growth inhibitory activities but displayed similar activities as inhibitors of tubulin polymerization. In addition, they led to the arrest of three cancer cell lines in the G2/M phase of the cell cycle and induced apoptosis. The disrupting in vitro effect of 2e, 2k and 2s on the vessel-like structures formed by human umbilical vein endothelial cells (HUVEC) suggest that these compounds may act as vascular disrupting agents. Both compounds, 2k and 2s, have the potential for further pro-drug modification and development as vascular disrupting agents for treatment of solid tumor cancers.

Domaines: Chimie thérapeutique; Chimie organique

Abdallah Hamze, Anne Giraud, Samir Messaoudi, Olivier Provot, Jean-François Peyrat, et al.. Synthesis, Biological Evaluation of 1,1-Diarylethylenes as a Novel Class of Antimitotic Agents. ChemMedChem, 2009, 4 (11), pp.1912-1924. ⟨10.1002/cmdc.200900290⟩. ⟨hal-02394586⟩